RU2542376C1 - Agent for pyoinflammatory processes in soft tissues and mucous membranes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: therapeutic agent contains carboxymethyl cellulose sodium salt as a base and a combination of antiseptic, 0.01% Myramistinum and metronidazole as therapeutic ingredients. The invention provides preparing the therapeutic agent possessing the antiseptic, wound-healing and sorption action on local pyoinflammatory processes in soft tissues and mucous membranes, used in surgery, dermatology, obstetrics and gynaecology, otorhinolaryngology.

EFFECT: agent possesses the higher efficacy.

2 tbl, 2 ex

Description

The invention relates to medicine, namely to agents with antimicrobial, wound healing and sorption effects on local purulent-inflammatory processes of soft tissues and mucous membranes used in surgery, dermatology, obstetrics and gynecology, otorhinolaryngology.

The urgent problem of modern surgery is the problem of treatment of purulent wounds, which is associated with the prevalence of wounds of various etiologies, purulent complications, high mortality, high material costs for treatment. According to some authors, purulent complications from all surgical diseases are 30-35%, and mortality from them reaches 25%.

Despite the development and implementation of new methods for treating purulent wounds, the use of medicines under a dressing is today the main one due to its availability, ease of use and economic benefits.

Among topical medicines, ointments and gels on the bases are widely used, which do not injure the damaged surface when applied to the wound, provide drainage of the wounds, and the medicinal substances included in their composition provide the necessary therapeutic effect. Without a doubt, modern drugs should have multidirectional effects and combine such properties as broad antimicrobial activity, high dehydrating ability, stimulation of tissue regeneration.

Antibacterial agents play a paramount role in the treatment of purulent-inflammatory processes, among which there is currently a significant increase in interest in antiseptics and chemotherapeutic agents, widely known and well-established in surgical practice, in particular, the imidazole group.

For the introduction of active substances, bases are used that have not only a good consistency, atraumatic when spreading, but also play the role of drainage and absorption of purulent discharge from the wound. Alloys of polyethylene oxides, gels of cellulose derivatives, etc. are widely used as such bases.

The prototype of the invention was a drug, which includes sodium hypochlorite on a gel of a polymer of sodium salt of carboxymethyl cellulose (NaKMTs) (patent for invention No. 2235535 from 2004.09.10 "Means for the treatment of local purulent-inflammatory processes of the skin and mucous membranes", patentee I. Nabokin I.I. .).

Sodium hypochlorite, despite its activity against many gram-positive and gram-negative bacteria, most pathogenic fungi, viruses and protozoa, is a very unstable compound, the effectiveness of which decreases rapidly in the presence of blood or its components. In addition, it has a characteristic smell of chlorine and has high corrosive properties, which negatively affects the well-being of staff and patients.

The technical result of the invention is the creation of a medicinal product with antiseptic, wound healing and sorption functions.

The technical result is achieved in that the agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes contains sodium carboxymethyl cellulose as a base, characterized in that it contains a combination of antiseptic agent 0.01% miramistin solution and metronidazole in the following mass fractions:

Miramistin solution 0.01% 95.0-100.0 (FS 42-3498-98) Metronidazole 1.0-2.0 (FS 42-2283-93) Carboxymethyl Cellulose Sodium 4.0-6.0 (TU 6-55-221-1453-96)

Feature Description

Miramistin (benzyldimethyl [3- (myristoylamino) propyl] ammonium chloride) - the original, patented drug, an antiseptic, belongs to the group of cationic surfactants, namely quaternary ammonium compounds. It has a pronounced bactericidal effect against gram-positive and gram-negative, aerobic and anaerobic bacteria in the form of monocultures and microbial associations, including hospital strains with antibiotic resistance.

Metronidazole. Antiprotozoal and antimicrobial drug derived from 5-nitroimidazole. The mechanism of action is the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. The reduced 5-nitro group of metronidazole interacts with the DNA of the cell of microorganisms, inhibiting the synthesis of their nucleic acids, which leads to the death of bacteria. Active against Trichomonas vaginalis, Gardnerella vaginalis, Giardia intestinalis, Entamoeba histolytica, Lamblia spp., As well as obligate anaerobes Bacteroides spp. (including Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus), Fusobacterium spp., Veillonella spp., Prevotella (Prevotella bivia, Prevotella buppae, Prevotella disppens.) Clostridium spp., Peptococcus spp., Peptostreptococcus spp., Mobiluncus spp.).

The sodium salt of carboxymethyl cellulose (NaKMTS) is soluble in water, in aqueous solutions of alkalis, in organic solvents and mineral oils - it is not soluble. In this case, the sodium salt of carboxymethyl cellulose forms viscous transparent solutions characterized by pseudoplasticity, and for some varieties of the product, by thixotropy (i.e., the ability to spontaneously restore the original structure destroyed by mechanical action). In the form of a gel, NaKMTs interacts with tissues and wound contents, is evenly distributed over the wound surface, provides fast and complete delivery of drugs to the lesion site, and exhibits an osmotic effect when applied to the wound, absorbing the wound discharge.

The method is as follows.

The manufacture of a medicine involves two steps.

First stage: the calculated amount of a 0.01% solution of miramistin is added to the corresponding sample of sodium salt of carboxymethyl cellulose, mixed and left for a day at a temperature of (4 ± 1) ° С to swell and obtain a homogeneous mass;

The second stage: to the pre-ground weighed portion of metronidazole, the obtained carboxymethyl cellulose sodium salt gel with a 0.01% miramistin solution is added in portions and mixed until a homogeneous mass is obtained.

Example No. 1 on the method of obtaining

To 4.0 mass fractions of NaCMC, add 100.0 mass fractions of a 0.01% miramistin solution, mix until smooth and leave for a day at a temperature of (4 ± 1) ° C, then to a pre-ground 1.0 mass fraction of metronidazole the resulting gel of the sodium salt of carboxymethyl cellulose with a 0.01% miramistin solution is added to the parts and mixed until a homogeneous mass is obtained.

Example No. 2 by the method of obtaining

To 6.0 mass fractions of NaCMC, 95.0 mass fractions of a 0.01% miramistin solution are added, mixed until a homogeneous mass is obtained and left for a day at a temperature of (4 ± 1) ° С, then to a pre-ground 2.0 mass fraction of metronidazole according to the resulting gel of the sodium salt of carboxymethyl cellulose with a 0.01% miramistin solution is added to the parts and mixed until a homogeneous mass is obtained.

Determination of the microbiological activity of a drug for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes.

The antimicrobial effect of the agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes (Example No. 1 and Example No. 2) was studied by agar diffusion (GF XII, 2007) in relation to St. strains. aureus ATCC 653 8-P, you. subtilis ATCC 6633, you. cereus ATCC 10702, E. coli ATCC 25922, Proteus vulgaris and Pseudomonas aeruginosa ATCC 9027, Candida albicans ATCC 885-653. The results of the determination of antimicrobial activity are presented in table 1.

From the data presented in table 1, it follows that the developed drug has a higher antimicrobial activity, which is due to the combination of an antiseptic and a chemotherapeutic drug, in relation to all the studied test strains. The growth retardation zone when studying the spectrum of antimicrobial activity of the developed ointment (example No. 1 and example No. 2) is most pronounced in relation to the test strains St. aure-us ATCC 653 8-P, E. coli ATCC 25922, which is 2.6 and 1.7 times larger than the growth inhibition zone in the study of the prototype (sodium hypochlorite solution at Na CMC), the differences between them are statistically significant.

Experimental Example

The study of the wound healing activity of the developed medicinal product was carried out in an experiment on male Wistar rats weighing 180-200 g, in which a purulent wound was modeled according to the method of P.I. Tolstoy (1976). The experimental animals were divided into three series, 36 animals each:

In the 1st series (model), treatment was not carried out.

In the 2nd series (control), they were treated with protopip (sodium hypochlorite at NaKMTS).

In the 3rd series, treatment was carried out with the agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes (example No. 1).

In the 4th series, treatment was carried out with the agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes (example No. 2).

Dressings were carried out daily. The course of the wound process in experimental animals was evaluated by planimetric (method of L.I. Popova), microbiological, histological methods, the results of the studies were processed statistically (calculated average values, reliability criterion). Animals were withdrawn from the experiment by an overdose of ether anesthesia on days 1, 3, 5, 8, 10, 15.

After modeling on the 1st day in all series, the wounds looked as follows: there was hyperemia, swelling of the surrounding tissues and edges of the wounds, their bottom was covered with plaque of fibrin with patches of necrosis, and abundant purulent discharge was observed.

During the treatment, the edema was stopped, the wound surface was cleansed of purulent necrotic masses, granulations appeared and edge epithelization started.

The results of a planimetric study indicate a faster decrease in the area of wounds in the 3rd and 4th series compared to the model and control (the initial area of the wounds was 250 mm ² ), by the 8th day the area of the wounds had statistically significant differences. The healing process proceeded faster in the 3rd and 4th series in comparison with the control and model. The results of a planimetric study are presented in table.2.

When comparing series 3 and 4, there were no statistically significant differences.

Thus, the obtained data of a planimetric study confirm the high efficiency of the developed tool for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes (example No. 1 and No. 2). It helps to reduce the area of wounds by 99.2% on the 15th day, increases the healing rate by 1.5-3.2 times in comparison with the control series.

The data of microbiological studies showed that in the 3rd and 4th series, the microbial contamination of the wounds was significantly less than in the control series starting from the 3rd day and throughout the observation period. In the 3rd and 4th series, on the 5th day, the microbial contamination of wounds is 5.4 times less than in the control series (15.2 ± 2.2 × 10 ⁵ , 18.4 ± 3.1 × 10 ⁵ and 8.1 ± 2.1 × 10 ⁶ CFU / g, respectively), on the 10th day - 18.3 times less than in the control series (33.3 ± 1.1 × 10 ³ , 40.1 ± 2.4 × 10 ³ and 6.1 ± 1.5 × 10 ⁵ CFU / g, respectively). Thus, it was found that the tool for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes (example No. 1 and No. 2) reduces the microbial contamination of wounds by 5.4-18.3 times compared with the prototype (sodium hypochlorite on NaKMTS).

For a complete assessment of the state of the wound in dynamics, the histological method of studying wound biopsy samples was used, which makes it possible to objectively assess the dynamics of the course of the wound process.

On the 1st day after modeling, the microscopic picture in all series is as follows. The entire surface of the wound is covered with a massive fibrinous-leukocyte layer. Most white blood cells are in a state of decay. The connective tissue under the leukocyte scab is sharply swollen, infiltrated by segmented leukocytes and single macrophages. The underlying connective tissue fiber is loosened, its fibroblasts are polymorphic, have a basophilic cytoplasm and swollen, loosened nuclei. The blood vessels are dilated. There are foci of hemorrhage of diapedetic nature. Edematous phenomena spread to the edges of the skin. The epithelium is dystrophic, vacuolated, its edge is flattened.

On the 3rd day in the group of animals in the control series, the surface of the wound is covered with a scab. The embryos of granulation tissue are infiltrated by polymorphonuclear leukocytes. On the 10th day, the formation of the epithelial shaft took place. Granulation tissue is delimited from the intact dermis and is infiltrated by polymorphic nuclear leukocytes. On the 15th day, the wound defect was performed by bundles of immature collagen fibers. The surface of the wound defect is covered by the epidermis, in which the stratum corneum was absent.

On the 3rd day, when using treatment for the purulent-inflammatory processes of soft tissues and mucous membranes (Example No. 1 and No. 2), there is a pronounced sharp border between granulations and intact skin, weak infiltration of newly formed granulations by polymorphic nuclear leukocytes. On the 10th day, a decrease in the volume of young collagen due to scar remodeling. The skin is restored in the area of the angle of the wound defect. On the 15th day, a complete restoration of the reticular layer of the skin was observed with the exception of derivatives: hair follicles and sebaceous glands.

In the series where the treatment was carried out with the agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes (Example No. 1 and No. 2), more rapid cleansing of the wound surface from leukocyte-necrotic masses (by the 3rd day) and a more active growth of granulation tissue. The beginning of the growth of the epithelium along the edges of the wound begins from 3 days. By the 7-10th day, a significant part of the wound or its entire surface is epithelized.

Thus, the use of the developed tool for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes in the I and II phases of the wound process increases the speed of wound healing by 1.5-3.2 times, helps to reduce the main stages of the course of the wound process by 1.3- 2.3 times, 5.4-18.3 times reduces microbial contamination of wounds, accelerates the formation and maturation of granulation tissue, promotes early and rapid epithelization of the wound surface, has high antimicrobial activity compared to the prototype treatment and acquiring (control lot).

Claims (1)

An agent for the treatment of purulent-inflammatory processes of soft tissues and mucous membranes containing sodium carboxymethyl cellulose as a base and including as a therapeutic component a combination of antiseptic agent 0.01% solution of miramistin and metronidazole in the following mass fractions:
Miramistin solution 0.01% 95.0-100.0 Metronidazole 1.0-2.0 Carboxymethyl Cellulose Sodium 4.0-6.0